title: Extracellular signal-regulated kinase 1/2 signaling pathway is required for endometrial decidualization in mice and human.
abstract: Decidualization is a crucial change required for successful embryo implantation and the maintenance of pregnancy. During this process, endometrial stromal cells differentiate into decidual cells in response to the ovarian steroid hormones of early pregnancy. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) are known to regulate cell proliferation and apoptosis in multiple cell types, including uterine endometrial cells. Aberrant activation of ERK1/2 has recently been implicated in the pathological processes of endometriosis and endometrial cancer. However, the function of ERK1/2 signaling during implantation and decidualization is still unknown. To determine the role and regulation of ERK1/2 signaling during implantation and decidualization, we examine ERK1/2 signaling in the mouse uterus during early pregnancy using immunostaining and qPCR. Interestingly, levels of phospho-ERK1/2 were highest within decidual cells located at the implantation sites. Expression levels of ERK1/2 target genes were also significantly higher at implantation sites, when compared to either inter-implantation sites. To determine if ERK1/2 signaling is also important during human endometrial decidualization, we examined levels of phospho-ERK1/2 in cultured human endometrial stromal cells during in vitro decidualization. Following treatment with a well-established decidualization-inducing steroidogenic cocktail, levels of phospho-ERK1/2 were markedly increased. Treatment with the ERK1/2 inhibitor, U0126, significantly decreased the expression of the known decidualization marker genes, IGFBP1 and PRL as well as inhibited the induction of known ERK1/2 target genes; FOS, MSK1, STAT1, and STAT3. Interestingly, the phosphorylation level of CCAAT/ enhancer binding protein β (C/EBPβ), a protein previously shown to be critical for decidualization, was significantly reduced in this model. These results suggest that ERK1/2 signaling is required for successful decidualization in mice as well as human endometrial stromal cells and implicates C/EBPβ as a downstream target of ERK1/2.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, Michigan, United States of America ; Department of Agricultural Biotechnology, Seoul National University, Seoul, South Korea.
authors.forename: Chae Hyun
authors.initials: CH
authors.lastname: Lee
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.forename: Jae Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Seo Jin
authors.initials: SJ
authors.lastname: Oh
authors.forename: Jung-Yoon
authors.initials: JY
authors.lastname: Yoo
authors.forename: Hyo Suk
authors.initials: HS
authors.lastname: Kwon
authors.forename: Young Im
authors.initials: YI
authors.lastname: Kim
authors.forename: Susan D
authors.initials: SD
authors.lastname: Ferguson
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Ahn
authors.forename: Bon Jeong
authors.initials: BJ
authors.lastname: Ku
authors.forename: Asgerally T
authors.initials: AT
authors.lastname: Fazleabas
authors.forename: Jeong Mook
authors.initials: JM
authors.lastname: Lim
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D003656:Decidua / Q000502:physiology*; D010064:Embryo Implantation / Q000502:physiology*; D005260:Female; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D011247:Pregnancy; D011388:Prolactin / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology
chemical_list: D002070:Butadienes; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C545012:CEBPB protein, human; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D009570:Nitriles; C113580:U 0126; D011388:Prolactin